ES2311690T3 - DEVICE AND PROCEDURE FOR SEPARATING RADIONUCLIDES EXEMPT FROM CARRIERS AND FOR THEIR RADIOCHEMICAL REACTION. - Google Patents

Abstract

The invention relates to a flow cell, a method for separating carrier-free radionuclides from a liquid or liquefiable target material, and the radiochemical reaction thereof. According to prior art, flow cells are known which require reaction volumes corresponding to the volume of the target material in order to carry out the desired reactions. The inventive flow cell ( 1 ) and method enable the reaction volume, and thus the quantity of starting material, to be reduced by a multiple by reducing the cylinder volume (=reaction volume). As the radioactively marked product is present in very small quantities (picomole to nanomole), the HPL-chromatographic separation of the non-reacted starting material is significantly improved. The economic efficiency of the method is increased due to the fact that small quantities of starting material can be used.

Description

Device and procedure to separate carrier-free radionuclides and for their reaction radiochemistry

The invention concerns a device and a procedure for the separation of radionuclides free of carriers from liquid or liquefiable target material and for radiochemical reaction thereof.

Radionuclides can be obtained by nuclear transformation procedures in a cyclotron, by example by bombardment of a suitable target with protons. A description of a procedure to separate exempt radionuclides of carriers from a target liquid is known, for example, by document DE 195 00 428.

It is also known by document DE 195 00 428 a device (flow cell) to separate exempt radionuclides of carriers from a target liquid, which consists substantially in a vitreous carbon cylinder (Sigradur®) and a platinum cannula axial through which a container is filled or emptied cylindrical or through which inert gas can be introduced into the camera. The system is immobilized by means of a bra plastic and sealed. At the inner end a funnel is formed plane that flows into the water drain pipe. In the head part of the bra are a pipe gas supply and an opening through which you can gas evacuated The vitreous carbon cylinder (Sigradur®) and the cannula plastic are connected to a direct current source and They can be discretionally connected as a cathode or as an anode. For obtaining the desired radionuclides, for example [18 F] fluoride from [18 O] H 2 O, se fill the flow cell with the target water it contains [18 F] fluoride. The [18 F] fluoride is deposited anodically on the surface of the cylinder and the 18 O-water is transported out. The height of the zone of [18 F] anodically fixed fluoride is identical to the filling level of the 18 O-water in the cell. So that the radioisotope fixed to the surface can be completely transferred to another liquid phase by inversion of the Polarity of the electric field is necessary to adapt the level of filled in the cell to the 18 O-water. So, for the next 18 F-fluorination one has to add a reaction volume that corresponds to that of the target water. This results in the need to adapt to this volume (for example, 1.3 ml) the amount of educts matter corresponding to the optimal concentration of educt. Due to the very small proportion Quantitative product matter (picobisnanomol) in comparison with the proportion of unreacted educt (\ mumol), this leads during debugging, especially during debugging chromatographic, at separation conditions difficulties. Given the the mass of the educt significantly exceeds the mass of the product, a HPL chromatographic separation runs, among other things, with just Poor resolution.

US 5,770,030 discloses a device for the separation of carrier-free radionuclides from a liquid or liquefiable target material and for the radiochemical reaction of the same. It is known by the Japanese document 2001-281131 a flow cell that presents a mobile piston that defines a slit with respect to a mobile cylinder within it.

Therefore, the problem of the invention consists in in creating a procedure and a device with which you can Reduce reaction volume. It is also a problem of invention reduce the amount of educt matter by a multiple while maintaining the optimum concentration of said educt.

Starting from the preamble of claim 1, the problem is solved according to the invention with the characteristics indicated in the characterizing part of claim 1. The problem is also solved by means of features indicated in the characterizing part of claim 14.

With the device and the procedure according to the invention is now possible to reduce the volume of reaction and, therefore, also the amount of educt through the cylinder volume reduction (= reaction volume). The Reduction of educt quantity simplifies debugging chromatographic and makes possible a quantitative separation of compounds marked as poor in carriers (product) since educt. Since more educt quantities can be used small, the costs are reduced and the profitability of the process.

The subordinate claims indicate advantageous improvements.

The drawings show an embodiment to example title of the procedure and the device according to the invention.

They show:

Figure 1, a cross section of the device in position I,

Figure 2, a cross section of the device in position II and

Figure 3, a plan view of the device in position II through the section plane A.

Figure 1 shows device 1 with a cylinder 2 provided with an embedded cannula 3 that is limited from below by means of a piston 4 with bore 5 that is connected with a cannula holder 7 through a yoke 6. Cylinder 2 can be filled with liquid or inert gas through the cannula 3. The device 1 is immobilized by a fastener 8 and sealed. In the part of fastener head 8 are two feed pipes 9 and 10 through which gases can be fed or evacuated. In the piston head 11 is a flat funnel 12 that flows into a hole 5. Cylinder 2 and cannula 3 are connected to a direct current source 13 and can be connected discretionally as a cathode or as an anode. In position I the cannula 3 is located at the lower end of cylinder 2. The piston 4 is outside the cylinder 2. In the lower zone 17 of the cylinder two seal rings 15 and 16 seal the piston 4 against the cylinder 2.

In Figure 2 they have been assigned reference symbols to the same characteristics of the device. Figure 2 shows the arrangement of the components of the device 1 in position II. In position II the piston 4 is inserted into cylinder 2. Cannula 3 is removed from the cylinder 2 in a measure corresponding to the height with which the piston 4 penetrates cylinder 2. Between piston 4 and cylinder 2 it has formed an annular slit 14. In Figure 2 a plane has been marked section in the lower area of the cylinder by means of the code "TO".

Figure 3 shows a plan view of the device 1 in position II through the section plane A. Between the piston 4 and the cylinder 2 the annular slit can be seen 14.

In the following the invention will be described Sample title

At the beginning of the reaction, the components of the device 1 may be placed, for example, as follows (see also figure 1; position I): The bottom opening of the cannula 3, which is preferably made of platinum, is in the lower end 17 of cylinder 2 and piston 4 is outside of cylinder 2. Device 1 is filled, through hole 5 or the pipe 6, with the target water it contains [18 F] fluoride, then depositing the [18 F] fluoride on the surface of cylinder 2, for which which applies a continuous voltage of, for example, 20 V to through a direct voltage source 13. Cannula 3 serves here of cathode Cylinder 2 is manufactured, in an advantageous embodiment of the device, in inert matter free of pores, such as, by example, vitreous carbon (Sigradur®), noble metal or platinum.

The piston 4 should preferably be made of inert material. It has been found to be suitable, for example, PEEK (polyether ether ketone), quartz glass or device glass. Without However, it is also possible to use a material piston electrically conductive, which can then also be used as electrode The slit width or the radius difference between the cylinder 2 and the piston 3 depend on the manufacturing methods. It has been found that a radio difference between the cylinder 2 and piston 4 of 0.4 mm. However, they are suitable also slit widths of? 0.2 mm. For the relationship of the spokes between the cylinder (r_ {1}) and the piston (r_ {2}) can Indicate the following equations:

F_ {1} = r_ {1} {} 2 * \pi

with F_ {= surface of cylinder 2

F_ {2} = r_ {2} {} 2 * \pi

with F 2 = piston surface 4

F_ {3} = F_ {1} - F 2 = \ pi (r_ {1} {} 2 - r_ {2})

with F 3 = surface of the slit 14

V_ {3} \ approx r_ {1} {} 2 - r_ {2} {} 2} \ approx (r_ {1} + r_ {2}) \ (r_ {1} - r_ {2})

with V_ {3} = slit volume 14

\ frac {V_ {1}} {V_ {3}} = \ frac {r_ {1} {} ^ {2}} {r_ {1} {} ^ {2} -r_ {2} {} 2}} = \ frac {r_ {1} {} 2}} {(r_ {1} + r_ {2}) (r_ {1} -r_ {2})}

with V_ {= cylinder volume 2.

After filling device 1 with the target solution (for example, 18 O-water) is deposits the radioisotope (for example, [18 F] fluoride) on the inner surface of the cylinder 2 and the 18 O-water out of device 1 through of hole 5 of piston 4. The height of the area of the [18 F] anodically fixed fluoride corresponds to the level 18 O-water filling in cylinder 2. A then the [18 F] fluoride fixed to the surface of cylinder 2 is completely transferred to another liquid phase by reversal of the polarity of the electric field, such as, by example, an organic solution containing catalyst of phase transfer ([K \ subset2.2.2] 2 C 2 O 4 in dimethyl sulfoxide = DMSO). It is necessary to adapt the filling level of this liquid phase in cylinder 2 at the level of pre-set filling of 18 O-water. For prevent, for the next [18 F] nucleophilic fluorination a corresponding reaction volume must be added to the water target, the piston dislodging effect is used 4. The piston 4 is transported up by displacement from yoke 6. At the same time, cannula 3 is removed from cylinder 3 in accordance with the height with which the piston 1 is inserted in cylinder 2. The volume that has to be loaded now in the cylinder 2 corresponds to the volume of the slit 14 that results when the piston 4 penetrates both the device 1 (see the figure 2, position II) that the upper end of the piston 4 coincides with the filling level of [18 F] fluoride set to the cylinder surface 2. In an advantageous embodiment of the device the volume ratio (V1) of cylinder 2 to Volume (V3) of slit 14 is approximately 4: 1 to 10: 1. In a particularly preferred embodiment of the device this Ratio is 4: 1. With a volume of 18 O-water of, for example, 1.3 ml, the volume of the slit 14, for a level identical filling, then amounts to approximately 0.25 ml. When the piston 4 is transported upwards in such a measure that the upper end of said piston 4 coincides with the level of filling of [18 F] fluoride fixed to the surface of the cylinder (see figure 2, position B), the [18 F] fluoride can be transferred to the solution of reaction by applying an electric field (Sigradur® as cathode). In this position, only the volume of the slit 14. The cylinder is sealed at the end bottom 17 against piston 4 by means of two ring seals 15 and 16 (for example, O-rings), so that an exit is prevented side of liquids at the lower end 17 of the cylinder.

To empty the reaction vessel is done the piston 4 goes down again and the liquid out through cannula 3 or drill 5 of the piston 4.

In an advantageous execution of the device and the procedure feeding or suction of the target water that contains [18 F] fluoride and the organic solvent is Performs through different pipes. When, for example, the target water feed containing [18 F] fluoride is carried out through the pipe 3, the transport of solvent organic used for desorption of the product must be carried out through hole 5 in order to avoid fouling of the pipe 3. Thus, for example, you can avoid a laborious cleaning of the pipe for the target water. Of course the target water transport can also be done through the drill 5 and organic solvent transport can be performed correspondingly through the pipe 3. Important for a simple device to handle and for the procedure is a separate pipe for different liquids.

By the procedure and the device according to The invention is possible to reduce the amount of educt. This mass reduction is advantageous especially for separation following chromatographic, from the educt, of the poor product in carriers labeled with 18 F. In procedures and devices known so far for the separation of radionuclides free of carriers and for the radiochemical reaction thereof is the amount of educt is significantly higher. Through the procedure and the device according to the invention is reduced by a multiple (by at least 3 to 4 times) the volume of the educto solution and, therefore, the amount of education, which significantly improves the chromatographic separation of educto and product marked with 18 F.

The reduction of the absolute amount of educt it also leads to cost savings and, therefore, to the improvement of The profitability of the procedure.

Execution Example Marking of N-methylbenperidol with 18 F

The 18 O-water (1.3 ml) which it contains [18 F] fluoride and that comes from the electrode cyclotron target is transported to device 1 through the hole 5 of the piston 4. Applying an electric voltage of 20 V a through direct current source 13 (anode = cylinder (2) of vitreous carbon) the poor radioisotope is adsorbed anodically in carriers on the surface of cylinder 2 within a time of approximately 8 minutes The 18 O-water is pressed out by means of helium through hole 5. The device is filled to dry the cylinder wall 1-2 times with, in each case, 1.6 ml of sulfoxide anhydrous dimethyl (DMSO) and said device is emptied through the cannula 3 that serves as a counter electrode. Through cannula 3 it load in device 1 a solution of 5 mg of crypto [K \ subset2.2.2] 2CO3 in 300 µl of DMSO) and displaces the engine piston 4 until the surface of the liquid reach the upper limit of [18 F] fluoride anodically separated. For the desorption of [18 F] fluoride voltage polarity is reversed (-2 V) and the cylinder is heated at approximately 100 ° C for 5 minutes After depolarization of the device the piston to the lower position and cannula 3 is added a 2 mg solution of N-methyl-desfluor-nitro-benperidol in 150 µl of DMSO. The piston 4 is moved back to the upper position and the device is heated at 150 ° C for 10 minutes It is then cooled with compressed air at temperature ambient. The device is emptied through cannula 3, washed this with about 0.8 ml of acetonitrile at 50 ° C and mixed this solution with the product-DMSO solution. Subsequent HPL chromatography purifies and isolates the radiotracer [18 F] N-methylbenperidol.

Claims (18)

1. Device (1) specially designed for the separation of carrier-free radionuclides from liquid or liquefiable target material and for the radiochemical radiation reaction thereof, comprising a cylinder (2), characterized by a piston (4) and a annular slit (14) between the cylinder (2) and the piston (4). 2. Device (1) according to claim 1, characterized in that the piston (4) has a circular cross-section and that the diameter of the piston (4) is smaller than the diameter of the cylinder (2). Device (1) according to one of claims 1 and 2, characterized in that the volume ratio between the cylinder (2) and the slit (14) is from 4: 1 to 10: 1. Device (1) according to one of claims 1 to 3, characterized in that the piston (4) comprises chemically inert material. Device (1) according to one of claims 1 to 4, characterized in that the piston (4) comprises PEEK, device glass, quartz glass or electrically conductive material. Device (1) according to one of claims 1 to 5, characterized in that the piston (4) has a bore (5). Device (1) according to one of claims 1 to 6, characterized in that the piston (4) has a centered bore (5). Device according to one of claims 1 to 7, characterized in that the cylinder (2) has an inert surface free of pores. Device (1) according to one of claims 1 to 8, characterized in that the cylinder (2) comprises a chemically inert material. Device (1) according to one of claims 1 to 9, characterized in that the cylinder (2) comprises vitreous carbon, noble metal or platinum. Device (1) according to one of claims 1 to 10, characterized in that the surface of the cylinder (2) is electrically charged during operation. 12. Device (1) according to one of claims 1 to 11, characterized in that it comprises a cannula (3) that is movable in the cylinder and is electrically charged. 13. Device (1) according to claim 12, as long as it depends on claim 11, characterized in that the cannula (3) is the counter electrode for the electrically charged cylinder (2). 14. Method for the separation of carrier-free radionuclides from liquid or liquefiable target material and for the radiochemical reaction thereof, characterized in that a device (1) according to one of claims 1 to 13 is used. 15. Method according to claim 14, characterized in that, after fixing the radionuclide on the surface of the cylinder (2), the piston (4) is introduced into the cylinder and at the same time the cannula (3) is removed from the cylinder in A corresponding measure. 16. Method according to one of claims 14 and 15, characterized in that the upper end of the piston (4) is moved to the level of filling of the target material in the cylinder (2). 17. Method according to one of claims 14 to 16, characterized in that the volume of the annular slit (14) formed between the piston (4) and the cylinder (2) is filled with a liquid phase. 18. Method according to claim 17, characterized in that after the desorption of the radionuclide in the liquid phase, the piston (4) is removed from the cylinder (2).